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Inflammation Dampened by Gelatinase A Cleavage of Monocyte Chemoattractant Protein-3

Science  18 Aug 2000:
Vol. 289, Issue 5482, pp. 1202-1206
DOI: 10.1126/science.289.5482.1202

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Abstract

Tissue degradation by the matrix metalloproteinase gelatinase A is pivotal to inflammation and metastases. Recognizing the catalytic importance of substrate-binding exosites outside the catalytic domain, we screened for extracellular substrates using the gelatinase A hemopexin domain as bait in the yeast two-hybrid system. Monocyte chemoattractant protein–3 (MCP-3) was identified as a physiological substrate of gelatinase A. Cleaved MCP-3 binds to CC-chemokine receptors–1, –2, and –3, but no longer induces calcium fluxes or promotes chemotaxis, and instead acts as a general chemokine antagonist that dampens inflammation. This suggests that matrix metalloproteinases are both effectors and regulators of the inflammatory response.

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